Matrix Metalloproteinases in Diabetic Kidney Disease

Abstract

Around the world diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD), which is characterized by mesangial expansion, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. The hallmark of the pathogenesis of DKD is an increased extracellular matrix (ECM) accumulation causing thickening of the glomerular and tubular basement membranes, mesangial expansion, sclerosis, and tubulointerstitial fibrosis. The matrix metalloproteases (MMPs) family are composed of zinc-dependent enzymes involved in the degradation and hydrolysis of ECM components. Several MMPs are expressed in the kidney; nephron compartments, vasculature and connective tissue. Given their important role in DKD, several studies have been performed in patients with DKD proposing that the measurement of their activity in serum or in urine may become in the future markers of early DKD. Studies from diabetic nephropathy experimental models suggest that a balance between MMPs levels and their inhibitors is needed to maintain renal homeostasis. This review focuses in the importance of the MMPs within the kidney and their modifications at the circulation, kidney and urine in patients with DKD. We also cover the most important studies performed in experimental models of diabetes in terms of MMPs levels, renal expression and its down-regulation effect.

Keywords: diabetic kidney disease; experimental models of diabetes; matrix metalloproteinases; tissue inhibitors of metalloproteinases.

Figure 1

Matrix metalloproteinases/Tissue inhibitors of metalloproteinases (MMPs/TIMP) activity and function in the extracellular matrix turnover. In diabetes the majority of MMPs are upregulated contributing actively to all stages of renal fibrosis formation and progression: inflammation, fibrotic type cell recruitment, stimulation of tubular epithelial-to-mesenchymal transition (EMT) and extracellular matrix (ECM) production and deposition.